Affecting ~ 25% of the general population worldwide, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease and is predicted to become increasingly prevalent, particularly among children and younger adults [1, 2]. NAFLD is a progressive disease that can further develop into non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma, and it is always accompanied by diabetes, cardiovascular disease, and chronic kidney disease, all of which will lead to an increased risk of mortality [3, 4]. The pathogenesis of NAFLD is not fully understood, which is associated with multiplex risk factors [5,6,7]: metabolic risk factors, gut microbiome composition, genetic factors, epigenetic factors, environmental risk factors, etc.
In recent years, the impact of iron metabolism on NAFLD has attracted renewed attention due to the proposal of “ferroptosis”, an iron-dependent form of cell death [8, 9]. Elena et al. [3] discovered that variants of genes related to iron metabolism are associated with high ferritin levels and increased hepatic iron in an Italian cohort of patients with NAFLD. Jordi et al. [10] showed that iron status influences liver fat accumulation in NAFLD through the gut microbiome. And a rat model of NAFLD exhibited systemic iron deficiency and hepatic iron overload [11]. The above studies support the notion that dysregulated iron homeostasis plays a role in the pathogenesis of NAFLD. And it was reported that a disturbance in iron metabolism affects one-third of patients with NAFLD [12]. However, the association between iron metabolism including serum levels of iron (SI), ferritin (SF), transferrin saturation (TSAT), and soluble transferrin receptor (sTfR) and NAFLD in general population has not been clearly established. Also, whether those biomarkers of iron metabolism could provide certain diagnostic value for NAFLD remains unknown.
Iron, a critical part of the hemoglobin of human beings [12], is essential for oxygen transportation, energy formation, and many cellular functions including DNA synthesis and repair [13, 14]. Iron cannot be naturally created by the human body, but must be ingested through diet or supplements [15]. For men and postmenopausal women, the recommended dietary allowance (RDA) of iron is 8 mg/day, whereas for premenopausal women, it is 18 mg/day according to the Institute of Medicine (US) (Institute of Medicine, 2001). Dietary iron is absorbed mainly in the duodenum and upper jejunum but is not enough for daily needs. The recycled iron from senescent or damaged erythrocytes in the spleen, liver, and bone marrow also contributes to iron storage [16]. Hepcidin is the master regulator for maintaining iron homeostasis, inducing degradation and internalization of the iron exporter ferroportin to inhibit the release of iron from recycling macrophages and absorption from dietary sources, thereby indirectly reducing iron entry into the bloodstream [17, 18]. The liver is the major site of iron storage [19] and plays a central part in iron homeostasis by producing hepcidin [18]. Therefore, liver diseases such as NAFLD may be more susceptible to iron status.
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The movement of iron between different cells and body tissues is mainly conducted by the transport protein transferrin, which plays a central role in iron metabolism. Each transferrin protein has two iron-binding domains that can reversibly bind two atoms of iron in a soluble nontoxic form [20, 21]. Serum iron (SI) consists of mostly transferrin-bound iron and a negligible amount of free non-transferrin-bound iron, which is toxic and was reported to promote oxidative stress [22, 23]. Ferritin is a major iron storage protein [24], and serum ferritin (SF) is the small quantity of ferritin circulating in the blood, which is regarded as a marker of iron stores in healthy individuals and those with early iron deficiency (ID). Transferrin saturation (TSAT), which indicates how many transferrin iron-binding sites are occupied, is considered an important biochemical marker of body iron status [25]. sTfR is a soluble form of transferrin receptor identified in serum [26] that reflects the demand for iron in cells and increases rapidly with the depletion of stored iron in the early stage of ID. Four biomarkers, SI, SF, TSAT, and sTfR, are indicators of iron metabolism and are commonly measured in clinics [25, 26].
Although several epidemiological studies have explored associations between biomarkers of iron metabolism and NAFLD, the conclusions were inconclusive and inconsistent. Jung et al. found that serum ferritin levels were positively associated with liver steatosis and fibrosis in the Korean general population [27]. Yang et al. [28] discovered that higher serum iron levels decreased the risk of NAFLD. And to the best of our knowledge, most studies have only evaluated the relationship between one index of iron metabolism and NAFLD. In this study, we comprehensively investigated the association between biomarkers of iron metabolism, including SI, SF, TSAT, and sTfR, and the prevalence of NAFLD in the general population of the U.S., utilizing data from the National Health and Nutrition Examination Survey (NHANES) collected from 2017 to 2018. And we have found that lower TSAT levels were significantly associated with a higher risk of NAFLD, which might provide additional information on biomarkers for the diagnosis of NAFLD. In addition, a controlled animal study was conducted to verify the results of the NHANES.
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